Our laboratory has previously shown that exposure to social disruption (SDR) the week prior to Theiler’s murine encephalomyelitis virus (TMEV) infection exacerbates disease course, resulting in increased infection-related sickness behaviors, motor impairment, CNS viral titers, and CNS inflammation. These adverse effects of SDR were prevented by ICV infusion of a neutralizing antibody to IL-6 during the stress exposure period. These findings suggest that stress-induced increases in IL-6 are necessary to exacerbate acute TMEV infection, but the exact mechanism remains unknown. This thesis tested the hypotheses that SDR up-regulates central cytokine expression, exacerbates TMEV infection through cross-sensitization of virus-induced cytokine expression, and that social rank modulates the effect of SDR. In Experiment 1, Balb/cJ mice underwent the 0, 1, or 6 SDR sessions and were then sacrificed 0, 2, or 12 hours post SDR. Experiment 2 subjects received ICV infusions of either IL-6 neutralizing antibody or its vehicle before each of six 2 h SDR sessions or the control condition, the week prior to infection. In Experiment 3 mice were tested for pre-existing social rank prior to SDR and infection. Results indicate that (1) SDR increases virus-induced IL-6, IL-1B, and CD11b mRNA expression in brain,that these SDR-induced increases and acute TMEV exacerbation are prevented by ICV infusion of the IL-6 neutralizing antibody during the stress exposure period, and that (2) social rank does not modulate affects of SDR but baseline anxiety does. These findings suggest that SDR exacerbates acute TMEV infection through cross-sensitization of virus-induced cytokine expression and that baseline anxiety is a significant modulator of SDR.

Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis activity has been commonly observed among breast cancer patients and has been linked to adverse health consequences. However, whether these alterations persist long after the cancer diagnosis has not been well-documented. In the first study, the diurnal cortisol rhythms and the cortisol stress response of breast cancer survivors who had completed all local and/or systemic adjuvant therapy with the exception of hormonal therapy were compared to those of women without a history of cancer. The Trier Social Stress Test was used to elicit a moderate stress response and the subjective levels of stress of participants were recorded using visual analog scales. The results indicate similar diurnal patterns in both groups; however, significant differences in stress reactivity were noted, with breast cancer survivors displaying a relatively flat profile following the acute stress induction. Subjective levels of psychological stress were similar in both groups, indicating that the subjective appraisal did not account for the blunted cortisol stress response. In the second study, the impact of the stressful life events that happened during the previous year on the cortisol stress response was analyzed in the same groups of participants. The frequency of stressful life events as well as their subjective impact was documented using the Life Experience Survey. Results suggest no group differences between the total number of stressful life events and their perceived effect. However, the number of stressful life events and their perceived impact correlated negatively with the peak cortisol concentration in breast cancer survivors. The results suggest that the cumulative effect of stressful life events contribute significantly to the low levels of cortisol reported in breast cancer survivors following a stressful situation. Together, these studies emphasize that breast cancer survivors are at risk of presenting a subtle alteration of their HPA axis activity when their system is challenged and that an accumulation of stressors plays a role in this dysregulation. These results reinforce the need for interventions intended to reduce the levels of psychological stress experienced by breast cancer survivors.

Production of the glucocorticoid hormone cortisol in response to a stressor is initiated by activation of the hypothalamic-pituitary-interrenal (HPI) axis in fish. Serotonin (5-HT) and negative feedback regulate cortisol production at the whole-animal level; the objective of the present thesis was to investigate their roles in regulating cortisol production by interrenal cells of rainbow trout (Oncorhynchus mykiss). Messenger ribonucleic acid (mRNA) for the 5-HT4 receptor was present in low abundance in interrenal cells. In addition, cortisol production was significantly increased for in vitro head kidney preparations incubated with 5-HT, and this elevated cortisol production was blocked by the 5-HT4 receptor antagonist 5-fluoro-2-methoxy-[1-[2-[(methylsulphonyl) amino] ethyl]-4-piperidinyl]-1h-indole-3-methylcarboxylate sulphamate (GR125487). Thus, 5-HT acts at the head kidney level to regulate cortisol production, probably via the 5-HT4 receptor. Chronic social stress did not appear to regulate the expression of key proteins involved in cortisol biosynthesis or corticosteroid receptors (CR). However, head kidney tissue incubated in vitro with cortisol for 2-8 h showed a reduction in adrenocorticotropic hormone-stimulated cortisol production compared to controls, suggesting the existence of an ultra-short-loop negative feedback mechanism. Thus, the high circulating levels of cortisol in trout experiencing chronic social stress may activate this ultra-short-loop negative feedback mechanism to suppress cortisol production at the head kidney level.

Many animals, including zebrafish (Danio rerio), form social hierarchies as a result of competition for limited resources. Socially subordinate fish experience chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis, leading to prolonged elevation of plasma cortisol, the glucocorticoid end-product of HPI axis activation. Elevated cortisol levels can reduce cellular proliferation and neurogenesis in the brain. Thus, the present study tested the hypothesis that social stress suppresses cellular proliferation in the brain of subordinate zebrafish via a cortisol-mediated mechanism. Cellular proliferation was assessed using the incorporation of 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue, as a marker. After 48 and 96 h of social interaction, significantly lower numbers of BrdU-positive cells were present in the forebrain of subordinate male zebrafish compared to dominant or control fish, suggesting a suppression of cellular proliferation in fish experiencing chronic social stress. Treatment of interacting male zebrafish with metyrapone, a cortisol synthesis inhibitor, attenuated the suppression of cellular proliferation in subordinate fish. Subordinate female zebrafish did not experience elevation of plasma cortisol or suppression of cellular proliferation in the forebrain. Collectively, these data provide evidence that cortisol plays a role in regulating cellular proliferation in the forebrain of male zebrafish during social interactions.

Polypterus senegalus is a basal ray-finned fish that breathes both air and water, and can tolerate life on land for extended periods. Previous research reported that P. senegalus held on land for several months exhibited lower growth rates than counterparts fed equal amounts of food but held under aquatic conditions. Because chronic stress can impair growth, the present research aimed to determine whether P. senegalus experience stress when held under terrestrial conditions. P. senegalus were held for 1, 2, 4, or 8 weeks in aquatic or terrestrial conditions, following which tissues were sampled for analysis. Growth rates were significantly lower in fish held under terrestrial conditions, but neither plasma cortisol levels nor transcript abundances of genes of the stress axis differed between aquatic and terrestrial fish. Terrestrial fish exhibited lower transcript abundance in liver of the growth regulator insulin-like growth factor 1, and higher transcript abundances in muscle of myostatin, an inhibitor of muscle growth, and muscle RING-finger protein-1, an indicator of muscle breakdown. With knowledge from anecdotal observations that P. senegalus tend to be aggressive when housed with a conspecific, P. senegalus were held in a second experiment in pairs for 6 d to investigate stress axis function. Clear differences in territorial and aggressive behaviours between the individuals in a pair were consistent with one fish being dominant over the other, subordinate fish. Dominant fish tended to have higher cortisol levels than subordinate fish, although the difference was not significant, and cortisol levels were correlated with the frequency of aggressive and territorial behaviours, regardless of social status. However, transcript abundances of stress axis genes generally did not differ between dominant and subordinate fish. Collectively, these results suggest that P. senegalus is unusually tolerant of conditions that serve as stressors in other fish species, including emersion and social interactions.

Juvenile rainbow trout (Oncorhynchus mykiss) held in pairs form dominance hierarchies, with subordinate individuals experiencing chronic social stress, as evidenced by prolonged elevation of the stress hormone cortisol. Prior work revealed that the thermal tolerance (measured as critical thermal maximum, CTmax) of subordinate fish was reduced, but the cause of this impairment was unknown. Here we tested the hypothesis that reduced thermal tolerance in subordinate trout is caused by prolonged elevation of circulating cortisol levels, affecting cardiac structure and function. In support of this hypothesis, subordinate trout that were allowed to recover from social stress for 48 h, a period sufficient to return cortisol to normal baseline levels, no longer showed a reduced CTmax. Furthermore, treatment of subordinates with cortisol to maintain elevated cortisol levels during the period of recovery from social stress prevented thermal tolerance from recovering. The possibility that prolonged elevation of cortisol levels induces cardiac remodelling in subordinate trout was explored by assessing heart histology and cardiac remodelling markers, and monitoring heart rate (fH). Picrosirius red staining revealed lower collagen levels in the ventricles of subordinate relative to dominant trout, although this difference was not accompanied by changes in collagen type I transcript abundances or protein levels, or by changes in markers of collagen turnover. Transcript abundances of markers of cardiac remodelling and ventricle mass were not significantly altered by chronic social stress. Heart rate in subordinates during social interactions was comparable to that in dominant fish. However, differences in fH responses of subordinate versus dominant fish were detected during acute warming. Specifically, peak heart rates tended to be observed at lower temperatures in subordinate fish relative to dominant. Thus, high baseline cortisol levels in subordinate trout result in lowered thermal tolerance, and chronic social stress has only minor effects on cardiac structure and function.

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The present study aimed to: (1) Characterize markers of reward sensitivity during periods of social stress using a well validated social feedback paradigm; (2) Evaluate clinical relations between reward markers and anhedonia; and (3) Investigate if elevated levels of baseline prior exposure to stress (i.e., peer victimization) are associated with the degree of ventral striatum suppression and anhedonia symptoms in a social stress context. A total of 29 adolescents between the ages of 13 and 17 years old (Mage = 15.31; SD = 1.51; 55.2% cisgender girls) participated in the present study. Participants were asked to complete a semi-structured interview; fill out self-report questionnaires regarding social anxiety, stress, depression, and anhedonia; and complete a magnetic resonance imaging scan while playing the Island Getaway task. Ventral striatum (VS) BOLD signal activation estimates were then extracted during discrete phases of the game (e.g., anticipation of social feedback and outcome of social feedback) and statistically compared within-subjects via paired samples t-tests and correlated to social anxiety measures. Additionally, regression analyses assessed the effect of VS activation on anhedonia as well as the associative effect of peer victimization on VS activation and anhedonia. Results revealed that when in the presence of social stress (defined as the potential for negative feedback), socially anxious adolescents demonstrated significantly suppressed VS activation relative to baseline when anticipating feedback. Additionally, results indicated that the degree of reduced VS activation during anticipation was correlated to total changes in anhedonia severity across the task. Lastly, results demonstrated that overt peer victimization is a significant predictor of suppressed VS activation during anticipation of social feedback, but not during social outcomes. Taken together, these results identify potentially novel mechanisms associated with anhedonia and blunted reward processing in socially anxious youth that could be improved via interventions that target positive-valence systems. / Doctor of Philosophy / Socially anxious teens may be at a heightened risk for developing anhedonia – which means that they are showing a significant lack of interest in things they used to find interesting or rewarding. This is problematic, because the presence of anhedonia is associated with not doing as well in therapy and even with higher rates of suicide attempt. One area that may be linked to the development of anhedonia in socially anxious teens is social stress induced disrupted reward processing in certain regions of the brain that generally activate when people anticipate a reward. Despite this, there is very little research on the development of anhedonia is socially anxious teens and even less that focuses on biological and behavioral experiences of reward processing when under social stress. This study examines this potential stress-to-anhedonia pipeline by looking at a key region of the brain, called the ventral striatum, to see if social stress does disrupt reward processing in socially anxious teens, and, if so, if this disrupted reward processing is related to anhedonia. Through evaluating a total of 29 socially anxious teens who underwent a social stress task while completing brain scanning, the present study demonstrated evidence for diminished brain activation in the ventral striatum when anticipating rewards. Additionally, the present study showed that reduced brain activation in the ventral striatum was associated with changes in anhedonia severity. Lastly, results from this study indicated that peer victimization (or bullying) was a significant predictor of diminished brain activation in the ventral striatum. Taken together, these results identify potentially new markers associated with anhedonia and blunted reward processing in socially anxious youth that could be improved via interventions.

Mindfulness – a receptive attentiveness to present experience – has been shown to promote more adaptive emotion regulation (Brown et al. 2008). Additionally, dispositional mindfulness has been shown to predict reduced cortisol response to social stressors (Brown et al, in press) and mindfulness training has been shown to promote more adaptive cardiac functioning at rest (Ditto et al., 2006; Tang et al., 2009; Telles et al., 2005; Zeidan et al., 2010) and in response to social stressors (Kemeny et al., 2012). To better understand the regulatory potential of a mindful disposition on cardiovascular functioning in healthy adult participants (N = 63), the study examined the role of dispositional mindfulness in predicting cardiovascular responses to a laboratory social evaluative threat called the Trier Social Stress Task (TSST; Kirschbaum, et al., 1993). Repeated measures multilevel linear modeling tested main effects of a mindful disposition on a variety of cardiovascular outcomes as well as interactive effects between mindfulness and time on these outcomes. Results showed that mindfulness predicted increased heart rate variability (HRV) across the time span, from baseline to recovery. There were also interactions between mindfulness and time on several dependent variables. Specifically, higher mindfulness predicted decreased heart rate reactivity during the TSST, faster recovery in total HRV, as well as reduced rebound effects during the initial recovery phase for high frequency HRV, low frequency HRV, and the LF/HF ratio. These results, however, were not significant above and beyond the significant relations between rumination, depressive symptoms, and trait anxiety and cardiovascular function. The results lend support to the stress-related regulatory potential of mindfulness, and suggest that this quality of attention may enhance cardiovascular functioning under stress. Further research is needed to examine how mindfulness may buffer the role of such vulnerability factors as rumination, depressive symptoms, and anxiety in predicting stress-related cardiovascular responses to social stress.